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• Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

  Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

  Study EGAS00001004405

• Oral Microbiome in Esophageal Adenocarcinoma

  The purpose of our study was to assess the influence of oral microbiota on the development of esophageal cancer. Our preliminary case-control studies reported a global alteration of foregut microbiome in esophageal adenocarcinoma with the strongest changes found in the oral microbiome. We hypothesise that commensal oral bacteria are capable of activating or degrading carcinogens in cigarette smoke and therefore may contribute to esophageal carcinogenesis. We conducted a prospective study nested in two large US cohorts, to determine whether oral microbiota are associated with subsequent esophageal adenocarcinoma.

  Study phs001527

• NHLBI TOPMed: Genetic Epidemiology Network of Salt Sensitivity (GenSalt)

  The GenSalt study aims to identify genes which interact with dietary sodium and potassium intake to influence blood pressure in Han Chinese participants from rural north China. Whole genome sequencing will be conducted among 1,860 participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study. We will work in collaboration with participating TOPMed studies to identify novel common, low-frequency and rare variants associated with an array of cardiometabolic phenotypes. In addition, we will explore the relation of low-frequency and rare variants with salt-sensitivity among GenSalt study participants.

  Study phs001217

• Genomic Analysis of Bevacizumab-induced Hypertension

  Bevacizumab use in the treatment of cancer can lead to the development of hypertension in some patients, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. In the present study, whole exomes and flanking regulatory regions of candidate genes associated with vasodilation and blood pressure were sequenced in bevacizumab-treated subjects with the objective of identifying genes harboring multiple variants associated with severe, early-onset bevacizumab-induced hypertension.

  Study phs001597

• Genetic measurement of memory B-cell recall using antibody repertoire sequencing

  We developed an improved high throughput sequencing approach to measure the quantities and sequences of the repertoire of antibody heavy chain RNA in a blood sample. Using this approach we analyzed the antibody repertoire in response to yearly vaccinations with influenza vaccines TIV and LAIV in healthy adults in two subsequent years. We determined vaccine response patterns specific to LAIV and TIV and found antibody sequences that were shared between two samples of the same individuals following influenza vaccination in subsequent years, thereby providing a genetic measurement of B-cell memory recall.

  Study phs000656

• Transcriptomic profiling of fragile X syndrome unmethylated full mutation carriers

  Total RNA sequencing of fibroblasts from two unrelated FMR1 unmethylated full mutation carriers, a fragile X patient and a control individual. The existence of rare, unmethylated full mutation carriers who carry the mutation that causes fragile X syndrome but do not gain methylation at the locus offers a rare opportunity to study the mechanisms underlying fragile X syndrome. This study aims to compare the transcriptomes of these four individuals in order to elucidate the mechanism behind the methylation a the FMR1 CGG repeat expansion that causes Fragile X syndrome.

  Study EGAS50000000647

• WES of Mino-VEN-R Mantle Cell Lymphoma Cells

  This project investigates the genetic basis of therapy resistance in mantle cell lymphoma (MCL) using whole exome sequencing (WES) of the Mino_VEN_R cell line, a model of resistance to pirtobrutinib, a non-covalent BTK inhibitor. Our study suggested that drug-tolerant persister (DTP) cells evade therapy through metabolic and phenotypic reprogramming. By analyzing the exome profile of resistant cells, this study aims to identify mutations associated with treatment escape and cellular plasticity. The findings will contribute to a better understanding of resistance mechanisms and support the development of more effective therapeutic strategies.

  Study EGAS50000001088

• Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas

  Intratumor heterogeneity and divergent clonal lineages within and among primary and recurrent hepatocellular carcinomas (HCCs) produce challenges to patient management. We investigated genetic and epigenetic variations within liver tumors, among hepatic lesions, and between primary and relapsing tumors. We performed whole-genome, whole-exome, or targeted capture sequencing analyses HCC specimens collected from multiple tumor regions and matched initial and recurrent tumors to obtain a systematic evaluation of intra- and intertumor genetic heterogeneity in HCC samples and to identify genetic changes associated with tumor progression and recurrence.

  Study EGAS00001002094

• Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild type primary glioblastoma

  We stratified 69 primary IDH-wt GBM patients into TMZ-resistant (n = 29) and sensitive (n = 40) groups, using TMZ screening of the corresponding patient-derived glioma stem-like cells (GSCs). Genomic and transcriptomic features were then examined to identify TMZ-associated molecular alterations. Subsequently, we developed a machine learning (ML) model to predict TMZ response from combined signatures. Moreover, TMZ response in multisector samples (52 tumor sectors from 18 cases) was evaluated to validate findings and investigate the impact of intra-tumoral heterogeneity on TMZ efficacy.

  Study EGAS00001006989

• Whole Genome sequencing of Angolan and Mozambican individuals

  To support the continued discovery and cataloguing of genomic variation in human populations and to further our understanding of the Bantu Expansion, we sequenced the genomes of 291 individuals from Cabinda, a northern exclave of Angola, and 49 individuals from Maputo, the capital of Mozambique. Utilising the power and flexibility of these whole-genome sequencing datasets, we discover rare variation, fine-scale population structure, and perform analyses using haplotype-based inference tools and our own model-based simulation framework to reconstruct complex dispersals of Bantu speak-ing populations across sub-Saharan Africa.

  Study EGAS00001007458

• Precursor_lesions__clonal_architecture_and_relapse_in_Wilms_nephroblastoma

  Targeted resequencing at high depth (21 genes, 9 chromosomal regions): at least 4 FFPE samples per case and matched germline DNA: •100 cases with detailed outcome data, including 15 cases with tumour relapse (515 samples)•40 cases with matched pre-chemotherapy biopsies (240 samples)•50 nephrogenic rests matched to above cases (50 samples)We expect a proportion (possibly 10%) of cases to be mutationally silent on the above studies, and propose to subsequently carry out integrated whole-genome, methylome and transcriptome studies on matched frozen tissue from these cases

  Study EGAS00001001422

• Myeloproliferative_Disorder_Sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 50 myeloproliferative disorder samples and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. In addition, 500bp, NO_PCR total genomic libraries will be prepared from the same samples and five lanes of Illumina GA sequencing will be analysed to characterise genome wide, somatically acquired structural variation.

  Study EGAS00001000198

• Myeloproliferative_Disorder_Sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 50 myeloproliferative disorder samples and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. In addition, 500bp, NO_PCR total genomic libraries will be prepared from the same samples and five lanes of Illumina GA sequencing will be analysed to characterise genome wide, somatically acquired structural variation.

  Study EGAS00001000199

• MutWP5__CRUK_Mutographs_of_Cancer__Cancer_Mastectomy__WG__Novaseq_

  Sequencing of LCM-derived microbiopsies from 40 women who underwent mastecomies due to breast cancer. LCM and sequencing will be conducted on both normal, unaffected breast, and, where possible, tumour tissue. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue, and compare findings between the normal and associated cancer tissues. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this poriton of the study will be compared to women who had cosmetic breast reduction surgeries and those who are BRCA carriers.

  Study EGAS00001003525

• RNASeq of PDX and CDX tumours treated with ADC

  Enapotamab vedotin (EnaV), an antibody-drug conjugate (ADC) targeting AXL, effectively targets tumors that display insensitivity to immunotherapy and/or tumor-specific T cells in several melanoma and lung cancer models. Mechanistically, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells, and promoted induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to any treatment alone in models of melanoma and lung cancer, and increased ICB benefit in models otherwise insensitive to anti-PD-1 treatment.

  Study EGAS00001004562

• RNA-sequencing of gluten-reactive and non-reactive T-cells from blood samples of treated CeD patients during a gluten-challenge

  Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Here we aimed to characterize such cells in blood of treated CeD patients during gluten challenge with comparison to similar cells of untreated disease. Treated CeD patients underwent a 3-day gluten-challenge with blood sampling at baseline and day 6 (d6). Blood cells were stained with HLA-DQ:gluten tetramers (Tetramer). CD4+, gut-homing Tetramer+ and Tetramer- effector-memory T (TEM) cells at d6 were subjected to bulk RNA-seq (n=7).

  Study EGAS00001004988

• H3Africa - Collaborative African Genomics Network

  Genomic studies have become one of the potential tools that could aid in the understanding of disease. HIV disease progression and active TB infection have been studied using these genomic methods to interrogate host factors associated with these diseases and their progression. Prior work has focused on adult populations and limited African cohorts. The Collaborative African Genomics Network aims to fill this gap by conducting HIV and TB disease mapping studies in African children to understand how genetic variation impacts disease progression through the use of genomic technologies.

  Study EGAS00001002656

• The mutational landscape of primary central nervous system lymphoma (Hipo H050, A050, XD013)

  ]Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) which are confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the mutational landscape in PCNSL, we here performed integrative whole genome and transcriptome sequencing analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL.

  Study EGAS00001005339

• Circular RNA characterization in functionally distinct brain regions

  Circular RNAs (circRNAs) represent a class of endogenous, non-coding RNAs that are formed when exons back splice to each other and that are both highly conserved and pervasively expressed in the mammalian brain. The goal of this study was thus to systematically identify and characterize circRNA expression and as well as to evaluate the predicted impact on regulatory networks in five functionally distinct cortical regions of healthy aged human brain - cerebellum (BC), inferior parietal lobe (IPL), middle temporal gyrus (MTG), occipital cortex (OC) and superior frontal gyrus (SGF).

  Study EGAS00001003128

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Cancer_Mastectomy__WG_

  Sequencing of LCM-derived microbiopsies from 40 women who underwent mastectomies due to breast cancer. LCM and sequencing will be conducted on both normal, unaffected breast, and, where possible, tumour tissue. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue, and compare findings between the normal and associated cancer tissues. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those who are BRCA carriers.

  Study EGAS00001003317

• Single-cell RNA and ATAC sequencing data analysis of human postmenopausal fallopian tube and ovary

  In this study, we used a combination of technologies, including Drop-seq, 10X single-cell RNA-seq (scRNA-seq), and single-cell assay on transposase accessible chromatin (scATAC-seq) to generate  a high-quality cell atlas that consists of four tissue sites from the reproductive tract of postmenopausal women. This atlas, by far the most comprehensive map of the postmenopausal female reproductive system to date, will pave the way to a better understanding of the pathophysiology of many diseases affecting older women.

  Study EGAS00001006780

• Leukemia sequencing study

  A custom single-cell amplicon DNA sequencing panel was designed to cover relevant somatic mutations and common single nucleotide polymorphisms (panel CO303). Frozen bone marrow mononuclear cells were thawed, stained using the antibody-derived tags panel TotalSeq™-D Human Heme Oncology Cocktail, V1.0 (Biolegend) and loaded into Tapestri single-cell DNA genotyping platform (Mission Bio) to perform microfluidic encapsulation, lysis, and barcoding according to the manufacturer’s protocol (Chemistry V2, PN_3360A). DNA and ADT libraries were prepared and underwent 2x150bp paired-end sequencing on a NextSeq 500 platform (Illumina).

  Study EGAS00001006784

• Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature

  To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki Disease (KD), bacterial infections and viral infections. Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020-April 2021 were prospectively recruited. Whole blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C to those from children with KD, definite bacterial and viral infections. Data deposited here comprises samples from patients recruited into the DIAMONDS study.

  Study EGAS00001007409

• Chordoma_Extension_Study

  Extension analysis to pursue candidate genes of interest in chordoma

  Study EGAS00001000892

• Chordoma_Extension__known_cancer_genes_

  Extension analysis to pursue candidate genes of interest in chordoma

  Study EGAS00001000895